Clear cell Renal Cell Carcinoma (ccRCC) represents the most prevalent subtype of Renal Cell Carcinoma, and was initially known as granular cell tumour, Grawitz tumour or hypernephrome.
ccRCC is an isolated and malignant lesion, which originates in the renal cortex. Renal proximal tubule cells are considered as the cell originating this type of malignant neoplasm. A rigorous examination shows the presence of a yellowish, round and well-defined lesion with multifocal hemorrhages and necrosis.
One of the major features of ccRCC is that it appears without specific symptoms and at least ⅓ of the patients have already a metastatic pattern at the time of diagnosis. Thus, ccRCC implies a great variety of non-specific clinical manifestations, going from the broadly known hematuria, pain and detectable renal mass, to the more complex paraneoplastic syndrome. Thus, the most common way to detect renal cell carcinomas in general is accidentally, during the performance of other diagnostic tests.
Nowadays, ccRCC are finally diagnosed from the visual analysis of biopsies of the kidney, or by means of ecography tools.
Biopsies are characterized by morphological cell features. ccRCC react with the antibody known as RCC disclosed by E. Oosterwdk, et al., “Monoclonal antibody G 250 recognizes a determinant present in renal-cell carcinoma and absent from normal kidney”, Int Journal of Cancer—1986, Vol. No. 38; pp. 489-494, which allows the distinction between metastatic lesions with clear cell features. Other immunostainings include the use of CD10, which is a glycoprotein that is particularly abundant in kidney, where it is present on the brush border of proximal tubules and on glomerular epithelium, and cytokeratins.
The patients can be treated by surgery being submitted to total or partial nephrectomy (kidney extirpation). Alternatively, patients are submitted to chemotherapeutic treatments with the multi-targeted receptor tyrosine kinase (RTK) inhibitor sunitinib of Pfizer.
An additional drawback of this type of cancer is that it may evolve to a worse or bad outcome (prognosis) depending on multifactor causes and because some patients are resistant to the treatments.
Thus, in case that a chemotherapeutical approach is to be applied, or a nephrectomy cannot be suggested for example due to possible complications derived from the patients profile (diabetes, advanced age, cardiovascular problems, etc.), the percentage of survival in case of ccRCC is low.
There is a need not only of specific markers for the diagnosis of ccRCC, but also of markers that can predict the prognosis of the disease. The definition of the outcome (prognosis) of ccRCC is of special interest in order to face the disease or to apply a correct therapy as soon as possible although other aspects of the health of the patients can be compromised.
At this regard, one of the tools employed for the prediction of the outcome of ccRCC is the Fuhrman system, in which each pathological level of the disease is defined by means of the nuclear features of the cells under study as follows: Grade I, cells have uniform and small nucleus; Grade II, cells with an open granular chromatin without evident nucleolus; Grade III, exacerbate nucleolus are identified; and Grade IV, defined by the presence of macronucleolus and of nuclear pleomorphism. The highest level identified in a specific lesion is the one determining the level of RCC.
Survival of patients diagnosed of ccRCC is well-correlated with the pathological level or grade. Thus, a great pathological level identified according to the Fuhrman grade, for example, is characterized by great-size tumours, extending through the renal vein or to perirenal fat. Metastasis of ccRCC is usually focused to the lung, bone and lymphatic nodes. Other less common invasion profiles include thyroid, heart spleen and pancreas, but only in cases of very disseminated ccRCC.
There exist several biochemical studies which try to correlate some molecules with the prognosis of renal neoplasms. Thus, in Guo et al., “Activation of STAT3 in renal tumors”, Am. J. Transl Res—2009, vol. 1(3), pp.: 283-290, it is disclosed that the transcription factor STAT3 is phosphorylated at the tyrosine residue Tyr705 in the 59.5% of ccRCC, and is also indicated as worse prognosis biomarker of renal neoplasms.
The document of Horiguchi et al., “Activation of signal transducer and activator of transcription 3 in renal cell carcinoma: A study of incidence and its association with pathological features and clinical outcome”, The Journal of Urology—2002, Vol. 168, pp. 762-765, is another example of document in which the STAT3 phosphorylated at the tyrosine residue Tyr705 is indicative of poor prognosis in case of renal cell carcinoma. In this document the authors indicate that a significant association of high levels of p-STAT3 correlated with metastasis, but no significant associations of p-STAT3 immunostaining with pathological stage or grade were observed. In this document tissue immunostaining is performed by pathologist classifying the activation of STAT3 in low or high based on the positive nuclear staining.
On the other hand, in the document of Komohara et al. “Macrophage infiltration and its prognostic relevance in clear cell renal cell carcinoma”, Japanese Cancer Association—2011, Vol. 102(4), pp.: 1424-1431, it is proposed to investigate a type of tumor-associated macrophages as markers for determining the outcome of ccRCC.
Finally, Kidney Injury Molecule 1 (KIM-1) has also been assessed to predict the outcome of different types of renal carcinomas, including ccRCC. An example of this is exposed in the document of Dong et al., “Expression and clinical significance of Kidney Injury Molecule 1 in renal epithelial neoplasms, PUBMED 20368397, Zhonguabing-2010,Vol. 39(1), pp. 35-39. The molecule, detectable by immunostaining, is presented as a usable more precise tool for histological classification and for a more accurate diagnosis.
Although there are some tools, indicia and markers for the diagnosis of ccRCC, and also there exist systems for determining the prognosis or outcome of the disease, alternative methods and tools are needed for providing more specific, sensitive and meaningful data at the same time they are methods or tools easy to be applied.